Thomas Dumortier (1), Didier Renard (1)
(1) Novartis Pharma, CH
Objectives: Secukinumab (Cosentyx®) is approved for the treatment of plaque psoriasis using a standard regimen of 300 mg Q4W administered subcutaneously. A question remained about potential suboptimal efficacy in heavy weight patients, and the higher exposure regimen 300 mg Q2W was investigated in a dedicated study in a population of patients > 90 kg. The study showed superiority in the primary efficacy endpoint (PASI 90) for the Q2W regimen compared to the approved Q4W regimen. It also showed a numerical benefit of uptitration in a subset of patients who did not achieve a PASI 90 response after 16 weeks of treatment with the standard regimen. The objectives of this work were to:
- Quantify precisely the benefit of uptitration in patients > 90 kg who do not achieve a PASI 90 response at Week 16 with the standard regimen
- Extrapolate the potential benefit of uptitration in patients ≤ 90 kg who do not achieve a PASI 90 response at Week 16 with the standard regimen.
Methods: A PK-PASI model was developed based on a large pool of data including >4000 patients. An indirect response model was used to characterize the dynamics over time and an augmented beta distribution was used to account for the bounded nature of the PASI endpoint and its inflated variability at the zero boundary. The dataset included a broad range of study designs (Ph1-2-3), dosing regimens, and body weights (36 – 219 kg). A subset of about 3000 patients was used for model fitting and the remaining subset served for model qualification. The new study in heavy weight patients was not included in this analysis and the model was used to make an external prediction of its outcome. The model was also used to predict the PASI response in patients ≤ 90 kg who do not achieve a PASI 90 response at Week 16 with the standard regimen.
Results: Overall, the model provided a good description of the pooled data (median PASI and various level of response, including PASI 50, PASI 75, PASI 90 and PASI 100). The model was also able to predict reasonably well the new study outcome, including in the overall study population and the subset of study patients who did not achieve a PASI 90 response at Week 16 with the 300 mg Q4W regimen. When used to make predictions in a more general population of heavy weight patients, the model predicted a significant benefit of about 20% in PASI 90 response rate when uptitrating the non-responder patients. Moreover, the model predicted a benefit of about 15% in a general population of non-responder patients <90 kg.
Conclusions: The PK-PASI model provided a precise estimate of the added benefit of uptitrating heavy weight patients who are PASI 90 non-responders and thus supported the use of the Q2W regimen in this particular population. It also enabled to extrapolate the benefit of the Q2W regimen to a broader population including non-responder patients < 90 kg, thereby showing that some patients < 90 kg may also benefit from dosing uptitration. These analyses were used to support a label update for flexible dosing of secukinumab in patients with plaque psoriasis (under health authority review).
Reference: PAGE 29 (2021) Abstr 9880 [www.page-meeting.org/?abstract=9880]
Poster: Clinical Applications